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Acute and chronic nociceptive phases observed in a rat hind paw ischemia/reperfusion model depend on different mechanisms

  • Ion channels, receptors and transporters
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Abstract

Complex regional pain syndrome type 1 (CRPS1) may be evoked by ischemia/reperfusion, eliciting acute and chronic pain that is difficult to treat. Despite this, the underlying mechanism of CRPS1 has not been fully elucidated. Therefore, the goal of this study is to evaluate the involvement of inflammation, oxidative stress, and the transient receptor potential ankyrin 1 (TRPA1) channel, a chemosensor of inflammation and oxidative substances, in an animal model of chronic post-ischemia pain (CPIP). Male Wistar rats were subjected to 3 h hind paw ischemia/reperfusion (CPIP model). Different parameters of nociception, inflammation, ischemia, and oxidative stress were evaluated at 1 (acute) and 14 (chronic) days after CPIP. The effect of a TRPA1 antagonist and the TRPA1 immunoreactivity were also observed after CPIP. In the CPIP acute phase, we observed mechanical and cold allodynia; increased levels of tumor necrosis factor-α (hind paw), ischemia-modified albumin (IMA) (serum), protein carbonyl (hind paw and spinal cord), lactate (serum), and 4-hydroxy-2-nonenal (4-HNE, hind paw and spinal cord); and higher myeloperoxidase (MPO) and N-acetyl-β-d-glucosaminidase (NAGase) activities (hind paw). In the CPIP chronic phase, we detected mechanical and cold allodynia and increased levels of IMA (serum), protein carbonyl (hind paw and spinal cord), and 4-HNE (hind paw and spinal cord). TRPA1 antagonism reduced mechanical and cold allodynia 1 and 14 days after CPIP, but no change in TRPA1 immunoreactivity was observed. Different mechanisms underlie acute (inflammation and oxidative stress) and chronic (oxidative stress) phases of CPIP. TRPA1 activation may be relevant for CRPS1/CPIP-induced acute and chronic pain.

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Abbreviations

ABSU:

Absorbance units

BCIP/NBT:

5-Bromo-4-chloro-3-indolyl phosphate/nitro blue tetrazolium

BSA:

Bovine serum albumin

CPIP:

Chronic post-ischemia pain

CRPS-I:

Complex regional pain syndrome I

DMSO:

Dimethyl sulfoxide

DNPH:

2,4-Dinitrophenylhydrazine

DTT:

1,4-Dithiothreitol

ELISA:

Enzyme-linked immunosorbent assay

4-HNE:

4-Hydroxy-2-nonenal

IMA:

Ischemia-modified albumin

MPO:

Myeloperoxidase

NAGase:

N-acetyl-β-d-glucosaminidase

PVDF:

Polyvinylidene difluoride

ROS:

Reactive oxygen species

TCA:

Trichloroacetic acid

TMB:

3,3′,5,5′-Tetramethyl-benzidine

TNF-α:

Tumor necrosis factor-α

TRPA1:

Transient receptor potential ankyrin 1

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Acknowledgments

This study was supported by the Conselho Nacional de Desenvolvimento Científico (CNPq) and by the Instituto Nacional de Ciência e Tecnologia (INCT) em Medicina Molecular (MCTI/CNPq, process number 471637.2013-0) and by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, process number 1444.2011) (Brazil). Fellowships from CNPq and CAPES are also acknowledged. We acknowledge Prof. Carlos Fernando Mello from the Federal University of Santa Maria for a critical reading of the manuscript. We would also like to acknowledge Dr. Arthur S Prudente and the Dr. Renata Tiscoski Nesi for the final revision of the figures in the manuscript.

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    Authors and Affiliations

    1. Grupo Multidisciplinar de Saúde, Programa de Pós-Graduação em Atenção Integral à Saúde, Universidade de Cruz Alta (UNICRUZ), 98020-290, Cruz Alta, RS, Brazil

      J. Z. Klafke

    2. Departamento de Saúde, Curso de Biomedicina, Faculdade de Educação e Cultura de Vilhena, 76980-000, Vilhena, RO, Brazil

      M. A. da Silva

    3. Programa de Pós-Graduação em Ciências Biológicas: Bioquímica Toxicológica, Departamento de Química, Universidade Federal de Santa Maria (UFSM), 97105-900, Santa Maria, RS, Brazil

      M. F. Rossato

    4. Programa de Pós-Graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense (UNESC), Avenida Universitária, 1105, room 21, building S, 88806-000, Criciúma, SC, Brazil

      S. Dal Toé de Prá & G Trevisan

    5. Programa de Pós-Graduação em Biomedicina do Instituto de Ensino e Pesquisa da Santa Casa de Belo Horizonte, Departamento de Biomedicina e Medicina (IEPBH), Belo Horizonte, MG, Brazil

      F. K. Rigo

    6. Departamento de Saúde (Farmácia), Universidade Federal do Sergipe (UFS), 49400-000, Lagarto, SE, Brazil

      C. I. B. Walker

    7. Programa de Pós-Graduação em Farmacologia, Departamento de Fisiologia e Farmacologia, Universidade Federal de Santa Maria (UFSM), 97105-900, Santa Maria, RS, Brazil

      G. V. Bochi & R. N. Moresco

    8. Laboratório de Bioquímica Clínica, Departamento de Análises Clínicas e Toxicológicas, Universidade Federal de Santa Maria (UFSM), 97105-900, Santa Maria, RS, Brazil

      J. Ferreira

    9. Programa de Pós-Graduação em Farmacologia, Departamento de Farmacologia, Universidade Federal de Santa Catarina (UFSC), Block “D”/CCB, Trindade, 88040-900, Florianópolis, SC, Brazil

      J. Ferreira

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    Correspondence to J. Ferreira or G Trevisan.

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    Author contributions

    All the authors discussed the results and commented on the manuscript, and approved this final version of the manuscript.

    1) Substantial contributions to conception and design, or acquisition of data, or analysis and interpretation of data: G Trevisan, J Z Klafke, M A da Silva, M F Rossato, S Dal Toé de Prá, F K Rigo, C I B Walker, G V Boch, R N Moresco, J Ferreira.

    2) Drafting the article or revising it critically for important intellectual content: G Trevisan, J Z Klafke, M A da Silva, M F Rossato, S Dal Toé de Prá, F K Rigo, C I B Walker, G V Boch, R N Moresco, J Ferreira.

    3) Final approval of the version to be published: G Trevisan, J Z Klafke, M A da Silva, M F Rossato, S Dal Toé de Prá, F K Rigo, C I B Walker, G V Boch, R N Moresco, J Ferreira.

    4) Acquisition of funding and general supervision of the research group: G Trevisan, J Z Klafke, R N Moresco, J Ferreira.

    5) Collection of data: G Trevisan, J Z Klafke, M A da Silva, M F Rossato, S Dal Toé de Prá, F K Rigo, C I B Walker, G V Boch.

    All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

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    J. Z. Klafke and G Trevisan contributed equally to this work.

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    Klafke, J.Z., da Silva, M.A., Rossato, M.F. et al. Acute and chronic nociceptive phases observed in a rat hind paw ischemia/reperfusion model depend on different mechanisms. Pflugers Arch - Eur J Physiol 468, 229–241 (2016). https://doi.org/10.1007/s00424-015-1746-9

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